Mechanisms of Leukemogenesis in Down Syndrome

唐氏综合症的白血病发生机制

• 批准号: 7322641
• 负责人: John D Crispino
• 金额: $ 30.57万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7322641
• 关键词: Acute Megakaryocytic Leukemias; Affect; Animals; Binding; Biological Assay; Bone Marrow; Cell Transplants; Cells; Child; Chromosomes, Human, Pair 21; Collaborations; Cytokine Signaling; Data; Defect; Development; Diagnostic; Diploidy; Disease; Down Syndrome; Embryo; Erythroid; Essential Genes; Etiology; Evolution; Exhibits; Face; Fetal Liver; Fetus; Flow Cytometry; Funding; GATA1 gene; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Programming; Goals; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Human; In Vitro; Infant; JAK2 gene; JAK3 gene; Janus kinase; Lead; Learning; Length; Link; Malignant Neoplasms; Megakaryocytes; Megakaryocytopoieses; Molecular Profiling; Monitor; Mouse Strains; Mus; Mutate; Mutation; Myelofibrosis; Myeloproliferative disease; N-terminal; Names; Orthologous Gene; Pathogenesis; Patients; Penetrance; Phenotype; Phosphotransferases; Pregnancy; Protein Isoforms; Protein Overexpression; Research; Research Personnel; Risk; Role; Sampling; Signal Transduction; Technology; Testing; Time; Transactivation; Transcription factor genes; Translations; Transplantation; Trisomy; Variant; Week; Work; Zinc Fingers; hematopoietic tissue; human GATA1 protein; improved; in vivo; insight; knock-down; leukemia; leukemogenesis; mouse Ts65Dn; mouse model; mutant; novel; progenitor; programs; small hairpin RNA; thrombocytosis; transient myeloproliferative disorder

DESCRIPTION (provided by applicant): Children with Down syndrome face a 10-20 fold increased risk of developing some form of leukemia and a 500-fold increased risk of acute megakaryoblastic leukemia (DS-AMKL). Furthermore, infants with DS are commonly and uniquely affected by a related myeloid disease, named transient myeloproliferative disorder (TMD). We recently demonstrated that the hematopoietic transcription factor GATA1 is mutated in nearly all cases of both TMD and DS-AMKL. In every case, the mutation results in loss of expression of full-length GATA-1, but allows for translation of a shortened isoform, GATA-1s, which retains both DMA binding zinc fingers, but is missing the N-terminal transactivation domain. We have found that GATA-1s can rescue the terminal differentiation of GATA-1 deficient megakaryocytes, but it fails to restrict their hyperproliferative phenotype: these observations lead us to hypothesize that an imbalance of gene regulation due to the expression of this short isoform contributes to the pathogenesis of TMD and DS-AMKL. With respect to the role of trisomy 21 in AMKL, we discovered that the most widely used mouse model of DS, Ts65Dn mice, develop a myeloproliferative disorder (MPD) characterized by thrombocytosis, myelofibrosis and a marked expansion in the megakaryocyte lineage. This suggests that trisomy 21 directly contributes to aberrant megakaryopoiesis and provides us with a platform for identifying the specific genes involved. Here we propose to define the role of GATA1 mutations and trisomy 21 in AMKL. Specifically we plan to: 1) characterize the myeloproliferative disease in mouse models of DS, 2) identify the mouse orthologs of human chromosome 21 genes that contribute to this disease (and, by extension, to DS-AMKL), and 3) assess the genetic interaction between GATA1, trisomy 21 and mutant forms of JAK kinases in AMKL, using mouse models. The results of our research will increase our understanding of how GATA1 mutations contribute to the initiation or progression of leukemia in DS and may also lead the identification of novel leukemia disease genes on human chromosome 21. In addition, since much leukemia, such as hyper- diploid ALL, acquire additional copies of chromosome 21 during their evolution; our work will likely have relevance to other more common forms of hematopoietic malignancies. Lay Summary: This research will provide insight to the cause of leukemia in children with Down syndrome and may lead to improved therapies and diagnostics. Furthermore, the research may also have impact on the etiology of other human blood diseases, such as myeloproliferative disorders.

描述（由申请人提供）：唐氏综合征儿童患某种形式白血病的风险增加10-20倍，患急性巨核细胞白血病（DS-AMKL）的风险增加500倍。此外，患有DS的婴儿通常和独特地受到相关骨髓疾病的影响，称为短暂性骨髓增生性疾病（TMD）。我们最近证明，造血转录因子GATA 1突变几乎所有的情况下，TMD和DS-AMKL。在每种情况下，突变导致全长加塔-1表达的丧失，但允许翻译缩短的同种型加塔-1 s，其保留两个DMA结合锌指，但缺失N-末端反式激活结构域。我们已经发现，加塔-1 s可以挽救加塔-1缺陷的巨核细胞的终末分化，但它不能限制它们的过度增殖表型：这些观察结果使我们假设，由于这种短亚型的表达导致的基因调控失衡有助于TMD和DS-AMKL的发病机制。关于21三体在AMKL中的作用，我们发现最广泛使用的DS小鼠模型Ts 65 Dn小鼠发生以血小板增多、骨髓纤维化和巨核细胞谱系显著扩增为特征的骨髓增殖性疾病（MPD）。这表明21三体直接导致异常巨核细胞生成，并为我们提供了一个平台，以确定特定的基因参与。在这里，我们建议确定AMKL中GATA 1突变和21三体的作用。具体而言，我们计划：1）表征DS小鼠模型中的骨髓增生性疾病，2）鉴定导致该疾病（并延伸至DS-AMKL）的人21号染色体基因的小鼠直系同源物，3）使用小鼠模型评估GATA 1、21三体和AMKL中JAK激酶突变形式之间的遗传相互作用。我们的研究结果将增加我们对GATA 1突变如何促进DS白血病的发生或进展的理解，也可能导致人类21号染色体上新的白血病基因的鉴定。此外，由于许多白血病，如超二倍体ALL，在其进化过程中获得21号染色体的额外拷贝;我们的工作可能与其他更常见形式的造血系统恶性肿瘤相关。简单总结：这项研究将为唐氏综合征儿童白血病的病因提供深入了解，并可能导致改进的治疗和诊断。此外，该研究还可能对其他人类血液疾病的病因学产生影响，如骨髓增生性疾病。